Reset Therapeutics proposes to develop orexin receptor agonists for the treatment of narcolepsy. Narcolepsy is a debilitating lifelong disorder characterized by excessive daytime sleepiness (EDS), cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucination and sleep paralysis. Narcolepsy affects approximately 150,000 people in the US and has a negative effect on the quality of life of its sufferers. It is well accepted that the primary cause of narcolepsy is due to orexin deficiency. The orexins are a pair of neuropeptides expressed by specific populations of neurons in the lateral hypothalamic area. The orexins act as a stabilizer of sleep/wake regulation in the brain and most patients that suffer from narcolepsy with cataplexy have low or undetectable levels of orexin in their cerebrospinal fluid. EDS associated with narcolepsy has historically been treated with stimulant medications including amphetamine and nonamphetamine formulations. Although these medications are effective, due to potential for addiction and negative side effects, newer nonstimulant wakefulness medications are preferred (e.g. modafinil). Currently, only one medication, sodium oxybate, is approved by the FDA for the treatment of cataplexy in narcoleptic patients. Sodium oxybate carries a black box warning and its distribution is restricted to the central pharmacy, due to its potential for abuse. Because of this, Reset anticipates that orexin receptor agonists could become the gold standard in narcolepsy treatment, due to the accepted cause of the disorder in humans. Reset's drug discovery program will utilize the four high priority chemical series that have already been obtained from a high throughput screen conducted to identify compounds active against the orexin receptors. Prioritization of these series will be completed through the use of an in vitro ADMET panel, made available through the NIH. New molecules will be synthesized using the NIH's selected chemistry CRO. The molecules will be designed to have improved potency, selectivity, stability and blood-brain barrier penetration. Reset's two in vivo models both contain significant innovations. The first model employs an in vivo emergence from anesthesia paradigm in order to efficiently measure the ability of lead compounds to positively affect consciousness. The proof of concept in vivo mouse model of narcolepsy utilizes proprietary sleep EEG software that is essential for reliably analyzing sleep stages in rodents. Compounds that pass through this critical path will progress into IND-enabling studies and Phase I clinical trials in collaboration with NIH contractors. PUBLIC HEALTH RELEVANCE: Narcolepsy is a debilitating lifelong sleep disorder that affects approximately 150,000 people in the US and has a negative effect on the quality of life of its sufferers. Current medications treat only the symptoms, mostly with amphetamines or other stimulants, are often only moderately effective and can have serious side effects; hampering their use. It is well accepted that the primary cause of narcolepsy is due to an orexin deficiency and thus Reset anticipates that orexin receptor agonists could provide a major improvement in the quality of life for narcoleptic patients and become the gold-standard in narcolepsy treatment. 1